2. Academic Validation
  3. Re-exploration of tetrahydro-β-carboline scaffold: Discovery of selective histone deacetylase 6 inhibitors with neurite outgrowth-promoting and neuroprotective activities

Re-exploration of tetrahydro-β-carboline scaffold: Discovery of selective histone deacetylase 6 inhibitors with neurite outgrowth-promoting and neuroprotective activities

  • Bioorg Med Chem Lett. 2024 Feb 21:102:129670. doi: 10.1016/j.bmcl.2024.129670.
Wen Wen 1,  Jiadong Hu 2,  Chenxi Wang 1,  Rui Yang 1,  Yabo Zhang 1,  Baibei Huang 1,  Tingting Qiao 1,  Jiayun Wang 3,  Xin Chen 4
Affiliations

Affiliations

  • 1 School of Medicinal and Chemical Engineering, Yangling Vocational & Technical College, Yangling 712100, PR China.
  • 2 School of Medicinal and Chemical Engineering, Yangling Vocational & Technical College, Yangling 712100, PR China. Electronic address: [email protected].
  • 3 Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, PR China.
  • 4 Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling 712100, PR China. Electronic address: [email protected].
PMID: 38387692 DOI: 10.1016/j.bmcl.2024.129670
Abstract

Histone deacetylase 6 (HDAC6) has drawn more and more attention for its potential application in Alzheimer's disease (AD) therapy. A series of tetrahydro-β-carboline (THβC) hydroxamic acids with aryl linker were synthesized. In enzymatic assay, all compounds exhibited nanomolar IC50 values. The most promising compound 11d preferentially inhibited HDAC6 (IC50, 8.64 nM) with approximately 149-fold selectivity over HDAC1. Molecular simulation revealed that the hydroxamic acid of 11d could bind to the zinc ion by a bidentate chelating manner. In vitro, 11d induced neurite outgrowth of PC12 cells without producing toxic effects and showed obvious neuroprotective activity in a model of H2O2-induced oxidative stress.

Keywords

HDAC6 inhibitor; Neurite outgrowth; Neuroprotective; Selectivity; THβC.

Figures
Products